There are large individual differences among humans and animals in behavioral, physiological and toxicological responses to drugs of abuse. Individual differences in human behavioral responses to drugs appear to display substantial genetic influences, although these influences may be provided by several genes. Family studies suggest several severe limitations to pedigree-based linkage approaches in drug abuse, suggesting that association studies might be more fruitful. Use of allelic association approaches also mandated careful examination of ethnic differences in populations and linkage disequilibrium at specific loci that can confound these approaches. Association studies with polymorphic markers at several different dopaminergic gene loci can test the hypothesis that interindividual differences in genes of dopaminergic neurotransmission could contribute to interindividual differences in vulnerability to substance abuse. During this fiscal year, this laboratory has continued to work to develop methods that would allow more sensitive detection of means whereby genes with allelic variants predisposing to substance abuse vulnerability could be identified. This work was accompanied by continuing work on possible confounding features, including racial and ethnic differences in marker frequencies, found in association studies. Studies of RFLP polymorphic markers at the mu opiate receptor locus failed to reveal allelic association in a number of the same research subjects. However, the association noted between substance abusers and higher frequencies of the TaqI A "allele" of the dopamine D2 receptor was found to be largely due to individuals who had access to drugs in several drug classes, but who preferred cocaine to opiates.